BIAXIN® Filmtab® (clarithromycin tablets, USP) BIAXIN® XL Filmtab® (clarithromycin extended-release tablets) BIAXIN® Granules (clarithromycin for oral suspension, USP) To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other antibacterial drugs, BIAXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C 38 H 69 NO 13 , and the molecular weight is 747.96. The structural formula is: Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. BIAXIN is available as immediate-release tablets, extended-release tablets, and granules for oral suspension. Reference ID: 3126038
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H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
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Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
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The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
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Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
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Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
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Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
H pylori negative shy H pylori positive - not eradicated eradicated
Sb Post-treatment susceptibility results
Ib Rb No MIC
Omeprazole 40 mg qdclarithromycin 500 mg tid for 14 days followed by omeprazole 20 mg qd for another 14 days (M93shy067 M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 1 1
Resistantb 4 4
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg tid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg bidclarithromycin 500 mg bid for 14 days followed by ranitidine bismuth citrate 400 mg bid for another 14 days (H2BA3001) Susceptible 125 106 1 1 12 5
Intermediateb 2 2
Resistantb 20 1 19
Omeprazole 20 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (126 127 M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 14 days (M95-399 M93-131 M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Lansoprazole 30 mg bidclarithromycin 500 mg bidamoxicillin 1 g bid for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a Includes only patients with pretreatment clarithromycin susceptibility tests b Breakpoints for antimicrobial susceptibility testing at the time of studies were Susceptible (S) MIC lt 025 mcgmL Intermediate (I) MIC 05-10 mcgmL Resistant (R) MIC gt 2 mcg mL For current antimictobial susceptibility testing guidelines see reference 4 For current susceptibility test interpretive criteria see Susceptibility Test for Helicobacter pylor below
Reference ID 3126038
Patients not eradicated of H pylori following omeprazoleclarithromycin ranitidine bismuth
citrateclarithromycin omeprazoleclarithromycinamoxicillin or lansoprazoleclarithromycin amoxicillin
therapy would likely have clarithromycin resistant H pylori isolates Therefore for patients who fail therapy
clarithromycin susceptibility testing should be done if possible Patients with clarithromycin resistant H
pylori should not be treated with any of the following omeprazoleclarithromycin dual therapy ranitidine
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
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Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs) These
MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds The MICs should be
determined using a standardized procedure Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of
clarithromycin powder The MIC values should be interpreted according to the following criteria2
Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcgmL) Interpretation le 20 Susceptible (S) 40 Intermediate (I) ge 80 Resistant (R)
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae a
MIC (mcgmL) Interpretation le 025 Susceptible (S) 05 Intermediate (I) ge 10 Resistant (R) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood
For testing Haemophilus sppb
MIC (mcgmL) Interpretation le 80 Susceptible (S) 160 Intermediate (I) ge 320 Resistant (R) b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp using Haemophilus Testing Medium (HTM)1
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable A report of Intermediate indicates that the result
should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically
feasible drugs the test should be repeated This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug can be used This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation A report of Resistant indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually achievable other therapy should
be selected
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test12 Standard clarithromycin powder should provide the following MIC ranges
Microorganism QC Strain MIC (mcgmL) S aureus ATCC reg29213c 012 to 05 S pneumoniaed ATCC 49619 003 to 012 Haemophilus influenzaee ATCC 49247 4 to 16 c ATCC is a registered trademark of the American Type Culture Collection d This quality control range is applicable only to S pneumoniae ATCC 49619 tested by microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5 lysed horse blood e This quality control range is applicable only to H influenzae ATCC 49247 tested by a microdilution procedure using HTM1
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds The zone size provides an estimate of the susceptibility
of bacteria to antimicrobial compounds The zone size should be determined using a standardized method23
The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of
bacteria The disc diffusion interpretive criteria are provided below
Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm) Interpretation ge 18 Susceptible (S) 14 to 17 Intermediate (I) le 13 Resistant (R)
Susceptibility Test Interpretive Criteria for Haemophilus sppg
Zone diameter (mm) Interpretation ge 21 Susceptible (S)
Reference ID 3126038
Zone diameter (mm) Interpretation ge 13 Susceptible (S) 11 to 12 Intermediate (I)
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
17 to 20 Intermediate (I) le 16 Resistant (R) f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5 sheep blood incubated in 5 CO2
For testing Haemophilus sppg
g These zone diameter standards are applicable only to tests with Haemophilus spp using HTM2
Note When testing Streptococcus pyogenes and Streptococcus pneumoniae susceptibility and resistance to clarithromycin can be predicted using erythromycin
Quality Control
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure
the accuracy and precision of supplies and reagents in the assay and the techniques of the individual
performing the test23 For the diffusion technique using the 15 mcg disc the criteria in the following table
should be achieved
Interpretation should be as stated above for results using dilution techniques Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for clarithromycin
As with standardized dilution techniques diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures For the diffusion
technique the 15-microg clarithromycin disk should provide the following zone diameters in this laboratory test
quality control strain
Acceptable Quality Control Ranges for Clarithromycin
Microorganism QC Strain Zone diameter (mm) S aureus ATCC 25923 26 to 32
S pneumoniaeh ATCC 49619 25 to 31
Haemophilus influenzaei ATCC 49247 11 to 17
h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5 defibrinated sheep blood i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2
Reference ID 3126038
In vitro Activity of Clarithromycin against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC)
microorganisms isolated from both AIDS and non-AIDS patients While gene probe techniques may be used
to distinguish M avium species from M intracellulare many studies only reported results on M avium
complex (MAC) isolates
Various in vitro methodologies employing broth or solid media at different pHs with and without oleic acidshy
albumin-dextrose-catalase (OADC) have been used to determine clarithromycin MIC values for
mycobacterial species In general MIC values decrease more than 16-fold as the pH of Middlebrook 7H12
broth media increases from 50 to 74 At pH 74 MIC values determined with Mueller-Hinton agar were 4- to
8-fold higher than those observed with Middlebrook 7H12 media Utilization of oleic acid-albumin-dextroseshy
catalase (OADC) in these assays has been shown to further alter MIC values
Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS
patients was evaluated using a microdilution method with Middlebrook 7H9 broth Results showed an MIC
value of le 40 mcgmL in 81 and 89 of the AIDS and non-AIDS MAC isolates respectively Twelve
percent of the non-AIDS isolates had an MIC value le 05 mcgmL Clarithromycin was also shown to be
active against phagocytized M avium complex (MAC) in mouse and human macrophage cell cultures as well
as in the beige mouse infection model
Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms In one study
utilizing the agar dilution method with Middlebrook 7H10 media 3 of 30 clinical isolates had an MIC of 25
mcgmL Clarithromycin inhibited all isolates at gt 100 mcgmL
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative
bacteria should not be used for determining clarithromycin MIC values against mycobacteria In vitro
susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory
concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been
standardized or validated Clarithromycin MIC values will vary depending on the susceptibility testing method
employed composition and pH of the media and the utilization of nutritional supplements Breakpoints to
determine whether clinical isolates of M avium or M intracellulare are susceptible or resistant to
clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H pylori is agar dilution MICs12 4One to three
microliters of an inoculum equivalent to a No 2 McFarland standard (1 x 107-1 x 108 CFUmL for H pylori)
are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5
Reference ID 3126038
aged defibrinated sheep blood (gt 2-weeks old) The agar dilution plates are incubated at 35degC in a
microaerobic environment produced by a gas generating system suitable for Campylobacter species After 3
days of incubation the MICs are recorded as the lowest concentration of antimicrobial agent required to
inhibit growth of the organism The clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria
Susceptibility Test Interpretive Criteria H pylor i Interpretation
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Susceptibility Test Interpretive Criteria for H pylori Interpretation
Amoxicillin MIC (microgmL) jk
lt 025 Susceptible (S) j These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods k There were not enough organisms with MICs gt 025 mcgmL to determine a resistance breakpoint
Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagentsa in the assay and the techniques of the individual performing the test Standard clarithromycin or amoxicillin powder should provide the following
MIC ranges
Acceptable Quality Control Ranges Microorganisms Antimicrobial Agent MIC (mcgmL) H pylori ATCC 43504 Clarithromycin 0015-012 microgmL H pylori ATCC 43504 Amoxicillin 0015-012 microgmL l These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets USP) and BIAXIN Granules (clarithromycin for oral suspension
USP) are indicated for the treatment of mild to moderate infections caused by susceptible isolates of the
designated bacteria in the conditions as listed below
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and
prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by
either the intramuscular or the oral route Clarithromycin is generally effective in the eradication of S
Reference ID 3126038
pyogenes from the nasopharynx however data establishing the efficacy of clarithromycin in the subsequent
prevention of rheumatic fever are not available at present)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Mycoplasma pneumoniae Streptococcus
pneumoniae or Chlamydia pneumoniae (TWAR)
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules as triple therapy are indicated for the treatment of
patients with H pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to
eradicate H pylori
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine
bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated
with H pylori infection However regimens which contain clarithromycin as the single antimicrobial agent
are more likely to be associated with the development of clarithromycin resistance among patients who fail
therapy Clarithromycin-containing regimens should not be used in patients with known or suspected
clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting
In patients who fail therapy susceptibility testing should be done if possible If resistance to clarithromycin is
demonstrated a non-clarithromycin-containing therapy is recommended (For information on development of
resistance see Microbiology section) The eradication of H pylori has been demonstrated to reduce the risk of
duodenal ulcer recurrence
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
PharyngitisTonsillitis due to Streptococcus pyogenes
Community-Acquired Pneumonia due to Mycoplasma pneumoniae Streptococcus pneumoniae or Chlamydia
pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Reference ID 3126038
Acute otitis media due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
NOTE For information on otitis media see CLINICAL STUDIES - Otitis Media
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes
(Abscesses usually require surgical drainage)
Disseminated mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with
mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions
listed below
Acute maxillary sinusitis due to Haemophilus influenzae Moraxella catarrhalis or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae Haemophilus
parainfluenzae Moraxella catarrhalis or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella
catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR
WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other
antibacterial drugs BIAXIN should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria When culture and susceptibility information are available they
should be considered in selecting or modifying antibacterial therapy In the absence of such data local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin erythromycin
or any of the macrolide antibiotics
Reference ID 3126038
Clarithromycin is contraindicated in patients with a history of cholestatic jaundicehepatic dysfunction
associated with prior use of clarithromycin
Concomitant administration of clarithromycin and any of the following drugs is contraindicated cisapride
pimozide astemizole terfenadine and ergotamine or dihydroergotamine (see Drug Interactions) There have
been post-marketing reports of drug interactions when clarithromycin andor erythromycin are coadministered
with cisapride pimozide astemizole or terfenadine resulting in cardiac arrhythmias (QT prolongation
ventricular tachycardia ventricular fibrillation and torsades de pointes) most likely due to inhibition of
metabolism of these drugs by erythromycin and clarithromycin Fatalities have been reported
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or
hepatic impairment
For information about contraindications of other drugs indicated in combination with BIAXIN refer to the
CONTRAINDICATIONS section of their package inserts
WARNINGS
Use In Pregnancy
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG THE PATIENT SHOULD BE APPRISED OF THE
POTENTIAL HAZARD TO THE FETUS CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME ANDOR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS RATS MICE AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO
17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES (See PRECAUTIONS - Pregnancy)
Hepatotoxicity
Hepatic dysfunction including increased liver enzymes and hepatocellular andor cholestatic hepatitis with
or without jaundice has been reported with clarithromycin This hepatic dysfunction may be severe and is
usually reversible In some instances hepatic failure with fatal outcome has been reported and generally has
been associated with serious underlying diseases andor concomitant medications Discontinue clarithromycin
immediately if signs and symptoms of hepatitis occur
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
receiving clarithromycin Fatalities have been reported Clarithromycin should be avoided in patients with
Reference ID 3126038
ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia clinically significant
bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine procainamide) or
Class III (dofetilide amiodarone sotalol) antiarrhythmic agents Elderly patients may be more susceptible to
drug-associated effects on the QT interval
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4
substrates These include colchicine toxicity with colchicine rhabdomyolysis with simvastatin lovastatin and
atorvastatin and hypotension with calcium channel blockers metabolized by CYP3A4 (eg verapamil
amlodipine diltiazem) (see PRECAUTIONS ndash Drug Interactions)
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and
colchicine Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both
drugs at their recommended doses If co-administration of clarithromycin and colchicine is necessary in
patients with normal renal and hepatic function the dose of colchicine should be reduced Patients should be
monitored for clinical symptoms of colchicine toxicity Concomitant administration of clarithromycin and
colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and
PRECAUTIONS ndash Drug Interactions)
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents
including BIAXIN and may range in severity from mild diarrhea to fatal colitis Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth of C difficile
C difficile produces toxins A and B which contribute to the development of CDAD Hypertoxin producing
strains of C difficile cause increased morbidity and mortality as these infections can be refractory to
antimicrobial therapy and may require colectomy CDAD must be considered in all patients who present with
diarrhea following antibiotic use Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents
If CDAD is suspected or confirmed ongoing antibiotic use not directed against C difficile may need to be
discontinued Appropriate fluid and electrolyte management protein supplementation antibiotic treatment of
C difficile and surgical evaluation should be instituted as clinically indicated
For information about warnings of other drugs indicated in combination with BIAXIN refer to the
WARNINGS section of their package inserts
Reference ID 3126038
PRECAUTIONS
General
Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria
Clarithromycin is principally excreted via the liver and kidney Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment and normal renal function However in the presence of
severe renal impairment with or without coexisting hepatic impairment decreased dosage or prolonged dosing
intervals may be appropriate
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with
creatinine clearance less than 25 mLmin (See DOSAGE AND ADMINISTRATION)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of
acute porphyria
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has
been reported in patients receiving clarithromycin therapy
For information about precautions of other drugs indicated in combination with BIAXIN refer to the
PRECAUTIONS section of their package inserts
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial
infections They do not treat viral infections (eg the common cold) When BIAXIN is prescribed to treat a
bacterial infection patients should be told that although it is common to feel better early in the course of
therapy the medication should be taken exactly as directed Skipping doses or not completing the full course
of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued
Sometimes after starting treatment with antibiotics patients can develop watery and bloody stools (with or
without stomach cramps and fever) even as late as two or more months after having taken the last dose of the
antibiotic If this occurs patients should contact their physician as soon as possible
BIAXIN may interact with some drugs therefore patients should be advised to report to their doctor the use of
any other medications
Reference ID 3126038
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk however
BIAXIN XL tablets should be taken with food Do NOT refrigerate the suspension
Drug Interactions
Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum
theophylline concentrations Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range In
two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 65 mgkg or 12 mgkg together with 250 or 500 mg q12h clarithromycin) the
steady-state levels of Cmax Cmin and the area under the serum concentration time curve (AUC) of theophylline
increased about 20
Hypotension bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent
verapamil belonging to the calcium channel blockers drug class
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine Blood level monitoring of carbamazepine may be
considered
When clarithromycin and terfenadine were coadministered plasma concentrations of the active acid
metabolite of terfenadine were threefold higher on average than the values observed when terfenadine was
administered alone The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions
Concomitant administration of clarithromycin with terfenadine is contraindicated
(See CONTRAINDICATIONS)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult
subjects The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0-24 and tfrac12
increases of 30 89 and 34 respectively) by the concomitant administration of clarithromycin The
mean 24-hour gastric pH value was 52 when omeprazole was administered alone and 57 when
coadministered with clarithromycin
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
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The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
PharyngitisTonsillitis due to S pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H influenzae M catarrhalis S pneumoniae
Acute exacerbation of chronic bronchitis due to H influenzae 500 mg 7-14 2 x 500 mg 7 H parainfluenzae 500 mg 7 2 x 500 mg 7 M catarrhalis 250 mg 7-14 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to H influenzae 250 mg 7 2 x 500 mg 7 H parainfluenzae - - 2 x 500 mg 7 M catarrhalis - - 2 x 500 mg 7 S pneumoniae 250 mg 7-14 2 x 500 mg 7 C pneumoniae 250 mg 7-14 2 x 500 mg 7 M pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -S aureus S pyogenes
H pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Triple therapy BIAXINlansoprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 30 mg lansoprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 or 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Triple therapy BIAXINomeprazoleamoxicillin
The recommended adult dose is 500 mg BIAXIN 20 mg omeprazole and 1 gram amoxicillin all given twice
daily (q12h) for 10 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) In
Reference ID 3126038
patients with an ulcer present at the time of initiation of therapy an additional 18 days of omeprazole 20 mg
once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINomeprazole
The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given
once daily (qAM) for 14 days (See INDICATIONS AND USAGE and CLINICAL STUDIES sections) An
additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief
Dual therapy BIAXINranitidine bismuth citrate
The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400
mg ranitidine bismuth citrate given twice daily (q12h) for 14 days An additional 14 days of 400 mg twice
daily is recommended for ulcer healing and symptom relief BIAXIN and ranitidine bismuth citrate
combination therapy is not recommended in patients with creatinine clearance less than 25 mLmin
(See INDICATIONS AND USAGE and CLINICAL STUDIES sections)
Children
The usual recommended daily dosage is 15 mgkgday divided q12h for 10 days
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight
Dosing Calculated on 75 mgkg q12h Weight Dose
Kg lbs (q12h) 125 mg5 mL 250 mg5 mL 9 20 625 mg 25 mL q12h 125 mL q12h
17 37 125 mg 5 mL q12h 25 mL q12h 25 55 1875 mg 75 mL q12h 375 mL q12h 33 73 250 mg 10 mL q12h 5 mL q12h
Mycobacterial Infections
Prophylaxis
The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500
mg bid In children the recommended dose is 75 mgkg bid up to 500 mg bid No studies of
clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses
recommended for prophylaxis are derived from MAC treatment studies in children Dosing recommendations
for children are in the table above
Treatment
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to
Mycobacterium avium complex Clarithromycin should be used in combination with other antimycobacterial
Reference ID 3126038
drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (See CLINICAL
STUDIES) The recommended dose for mycobacterial infections in adults is 500 mg bid In children the
recommended dose is 75 mgkg bid up to 500 mg bid Dosing recommendations for children are in the
table above
Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed
Constituting Instructions
The table below indicates the volume of water to be added when constituting
Total Volume After Constitution Clarithromycin Concentration After Constitution
Amount of Water to be Added
50 mL 100 mL 50 mL
100 mL
125 mg5 mL 125 mg5 mL 250 mg5 mL 250 mg5 mL
27 mL 55 mL 27 mL 55 mL
see instructions below
Add half the volume of water to the bottle and shake vigorously Add the remainder of water to the bottle and
shake
Shake well before each use Oversize bottle provides shake space Keep tightly closed Do not refrigerate
After mixing store at 15deg to 30degC (59deg to 86degF) and use within 14 days
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets USP) are supplied as yellow oval film-coated tablets in the following
packaging sizes
250 mg tablets (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11)
Store BIAXIN 250 mg tablets at controlled room temperature 15deg to 30degC (59deg to 86degF) in a well-closed
container Protect from light
500 mg tablets (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11)
Store BIAXIN 500 mg tablets at controlled room temperature 20deg to 25degC (68deg to 77degF) in a well-closed
container
Reference ID 3126038
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg
tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation KJ in the
following packaging sizes
500 mg tablets
Bottles of 60 (NDC 0074-3165-60) ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11) and
BIAXIN XL PAC carton of 4 blister packages 14 tablets each (NDC 0074-3165-41)
Store BIAXIN XL tablets at 20deg to 25degC (68deg to 77degF) Excursions permitted to 15deg to 30degC (59deg to 86degF)
[See USP Controlled Room Temperature]
BIAXIN Granules (clarithromycin for oral suspension USP) is supplied in the following strengths and sizes
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of
clarithromycin may be underestimated
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of bacteremia patients in the group randomized to clarithromycin
showed reductions in the signs and symptoms of disseminated MAC disease including fever night sweats
weight loss and anemia
Safety
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M avium it
was often difficult to distinguish adverse events possibly associated with clarithromycin administration from
underlying HIV disease or intercurrent illness Median duration of treatment was 106 months for the
clarithromycin group and 82 months for the placebo group
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients Receiving Prophylaxis Against M avium Complex
Body SystemDagger
Adverse Event Clarithromycin
(n = 339)
Placebo (n = 339)
Body as a Whole
Abdominal pain Headache
50 27
35 09
Digestive Diarrhea 77 41 Dyspepsia Flatulence
38 24
27 09
Nausea 112 71 Vomiting
Skin amp Appendages Rash
59
32
32
35
Special Senses
Taste Perversion 80 03 Includes those events possibly or probably related to study drug and excludes concurrent conditions Dagger gt 2 Adverse Event Incidence Rates for either treatment group
Among these events taste perversion was the only event that had significantly higher incidence in the
clarithromycin-treated group compared to the placebo-treated group
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
Discontinuation due to adverse events was required in 18 of patients receiving clarithromycin compared to
17 of patients receiving placebo in this trial Primary reasons for discontinuation in clarithromycin treated
patients include headache nausea vomiting depression and taste perversion
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against M avium evaluations of laboratory values
were made by analyzing those values outside the seriously abnormal value (ie the extreme high or low limit)
for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M avium Complex
Clarithromycin Placebo 500 mg bid
Hemoglobin
Platelet Count
lt 8 gdL
lt 50 x 109L
4118 3
11249 4
5103 5
12250 5
WBC Count lt 1 x 109L 2103 4 095 0
SGOT gt 5 x ULN(b) 7196 4 5208 2
SGPT gt 5 x ULN(b) 6217 3 4232 2
Alk Phos gt 5 x ULN(b) 5220 2 5218 2
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) ULN = Upper Limit of Normal
Treatment
Three randomized studies (500 577 and 521) compared different dosages of clarithromycin in patients with
CDC-defined AIDS and CD4 counts lt 100 cellsmicroL These studies accrued patients from May 1991 to March
1992 Study 500 was randomized double-blind Study 577 was open-label compassionate use Both studies
used 500 and 1000 mg bid doses Study 500 also had a 2000 mg bid group Study 521 was a pediatric
study at 375 75 and 15 mgkg bid Study 500 enrolled 154 adult patients Study 577 enrolled 469 adult
patients and Study 521 enrolled 25 patients between the ages of 1 to 20 The majority of patients had CD4 cell
counts lt 50microL at study entry The studies were designed to evaluate the following end points
1 Change in MAC bacteremia or blood cultures negative for M avium
2 Change in clinical signs and symptoms of MAC infection including one or more of the following fever
night sweats weight loss diarrhea splenomegaly and hepatomegaly
Reference ID 3126038
The results for the 500 study are described below The 577 study results were similar to the results of the 500
study Results with the 75 mgkg bid dose in the pediatric study were comparable to those for the 500 mg
bid regimen in the adult studies
Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus
clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC
(dMAC) infection4 5This 24-week study enrolled 106 patients with AIDS and dMAC with 55 patients
randomized to receive clarithromycin and ethambutol and 51 patients randomized to receive clarithromycin
ethambutol and clofazimine Baseline characteristics between study arms were similar with the exception of
median CFU counts being at least 1 log higher in the clarithromycin ethambutol and clofazimine arm
Compared to prior experience with clarithromycin monotherapy the two-drug regimen of clarithromycin and
ethambutol was well tolerated and extended the time to microbiologic relapse largely through suppressing the
emergence of clarithromycin resistant strains However the addition of clofazimine to the regimen added no
additional microbiologic or clinical benefit Tolerability of both multidrug regimens was comparable with the
most common adverse events being gastrointestinal in nature Patients receiving the clofazimine-containing
regimen had reduced survival rates however their baseline mycobacterial colony counts were higher The
results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC
infections but do not support adding clofazimine as a third agent
MAC Bacteremia
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose
groups Mean reductions in colony forming units (CFU) are shown below Included in the table are results
from a separate study with a four drug regimen56 (ciprofloxacin ethambutol rifampicin and clofazimine)
Since patient populations and study procedures may vary between these two studies comparisons between the
clarithromycin results and the combination therapy results should be interpreted cautiously
Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg bid 1000 mg bid 2000 mg bid Four Drug Regimen
(N = 35) (N = 32) (N = 26) (N = 24) 15 23 23 14
Although the 1000 mg and 2000 mg bid doses showed significantly better control of bacteremia during the
first four weeks of therapy no significant differences were seen beyond that point The percent of patients
whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was
61 (3049) for the 500 mg bid group and 59 (2949) and 52 (2548) for the 1000 and 2000 mg bid
groups respectively The percent of patients who had 2 or more negative cultures during acute therapy that
were sustained through study Day 84 was 25 (1249) in both the 500 and 1000 mg bid groups and 8
(448) for the 2000 mg bid group By Day 84 23 (1149) 37 (1849) and 56 (2748) of patients had
Reference ID 3126038
died or discontinued from the study and 14 (749) 12 (649) and 13 (648) of patients had relapsed in
the 500 1000 and 2000 mg bid dose groups respectively All of the isolates had an MIC lt 8 mcgmL at
pre-treatment Relapse was almost always accompanied by an increase in MIC The median time to first
negative culture was 54 41 and 29 days for the 500 1000 and 2000 mg bid groups respectively The time
to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days respectively) in comparison to the 500 mg bid group (median equal
to 29 days) The median time to first positive culture or study discontinuation following the first negative
culture was 43 59 and 43 days for the 500 1000 and 2000 mg bid groups respectively
Clinically Significant Disseminated MAC Disease
Among patients experiencing night sweats prior to therapy 84 showed resolution or improvement at some
point during the 12 weeks of clarithromycin at 500 to 2000 mg bid doses Similarly 77 of patients
reported resolution or improvement in fevers at some point Response rates for clinical signs of MAC are
given below
Resolution of Fever Resolution of Night Sweats bid ever bid ever dose afebrile afebrile dose resolving resolving (mg) ge 6 weeks (mg) ge 6 weeks 500 67 23 500 85 42
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
The median duration of response defined as improvement or resolution of clinical signs and symptoms was 2
to 6 weeks
Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks the duration of
response may be underestimated for the 25 to 33 of patients who continued to show clinical response after
12 weeks
Survival
Median survival time from study entry (Study 500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose However during the first 12 weeks of therapy there were 2 deaths in 53
patients in the 500 mg bid group versus 13 deaths in 51 patients in the 1000 mg bid group The reason for
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
this apparent mortality difference is not known Survival in the two groups was similar beyond 12 weeks The
median survival times for these dosages were similar to recent historical controls with MAC when treated with
combination therapies56
Median survival time from study entry in Study 577 was 199 days for the 500 mg bid dose and 179 days for
the 1000 mg bid dose During the first four weeks of therapy while patients were maintained on their
originally assigned dose there were 11 deaths in 255 patients taking 500 mg bid and 18 deaths in 214
patients taking 1000 mg bid
Safety
The adverse event profiles showed that both the 500 and 1000 mg bid doses were well tolerated The 2000
mg bid dose was poorly tolerated and resulted in a higher proportion of premature discontinuations
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over
long periods of time for mycobacterial infections it was often difficult to distinguish adverse events possibly
associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin Data
are reported separately for Study 500 (randomized double-blind) and Study 577 (open-label compassionate
use) and also combined Adverse events were reported less frequently in Study 577 which may be due in part
to differences in monitoring between the two studies In adult patients receiving clarithromycin 500 mg bid
the most frequently reported adverse events considered possibly or probably related to study drug with an
incidence of 5 or greater are listed below Most of these events were mild to moderate in severity although
5 (Study 500 8 Study 577 4) of patients receiving 500 mg bid and 5 (Study 500 4 Study 577
6) of patients receiving 1000 mg bid reported severe adverse events Excluding those patients who
discontinued therapy or died due to complications of their underlying non-mycobacterial disease
approximately 8 (Study 500 15 Study 577 7) of the patients who received 500 mg bid and 12
(Study 500 14 Study 577 12) of the patients who received 1000 mg bid discontinued therapy due to
drug-related events during the first 12 weeks of therapy Overall the 500 and 1000 mg bid doses had similar
adverse event profiles
Treatment-related Adverse Event Incidence Rates () in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg bid Clarithromycin Dose
Adverse Event Study 500 Study 577 Combined (n = 53) (n = 255) (n = 308)
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
Taste Perversion 189 04 36 Vomiting 245 39 75 Includes those events possibly or probably related to study drug and excludes concurrent conditions
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for
mycobacterial infections The most frequently reported adverse events excluding those due to the patients
concurrent condition were consistent with those observed in adult patients
Changes in Laboratory Values
In immunocompromised patients treated with clarithromycin for mycobacterial infections evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level (ie the extreme
high or low limit) for the specified test
Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg bid Dose(b)
Study 500 Study 577 Combined BUN
Platelet Count
gt 50 mgdL
lt 50 x 109L
0
0
lt 1
lt 1
lt 1
lt 1
SGOT gt 5 x ULN(c) 0 3 2
SGPT gt 5 x ULN(c) 0 2 1
WBC lt 1 x 109L 0 1 1
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) (b) Includes all values within the first 12 weeks for patients who start on 500 mg bid (c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States where significant rates of
beta-lactamase producing organisms were found clarithromycin was compared to an oral cephalosporin In
this study very strict evaluability criteria were used to determine clinical response For the 223 patients who
were evaluated for clinical efficacy the clinical success rate (ie cure plus improvement) at the post-therapy
visit was 88 for clarithromycin and 91 for the cephalosporin
In a smaller number of patients microbiologic determinations were made at the pre-treatment visit The
following presumptive bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
US Acute Otitis Media Study Clarithromycin vs Oral Cephalosporin EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 1315 (87) control 45 H influenzae clarithromycin success rate 1014 (71) control 34 M catarrhalis clarithromycin success rate 45control 11 S pyogenes clarithromycin success rate 33control 01
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
Overall clarithromycin success rate 3037 (81) control 811 (73) None of the H influenzae isolated pre-treatment was resistant to clarithromycin 6 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea and vomiting did not differ
clinically or statistically for the two agents
In two other controlled clinical trials of acute otitis media performed in the United States where significant
rates of beta-lactamase producing organisms were found clarithromycin was compared to an oral
antimicrobial agent that contained a specific beta-lactamase inhibitor In these studies very strict evaluability
criteria were used to determine the clinical responses In the 233 patients who were evaluated for clinical
efficacy the combined clinical success rate (ie cure and improvement) at the post-therapy visit was 91 for
both clarithromycin and the control
For the patients who had microbiologic determinations at the pre-treatment visit the following presumptive
bacterial eradicationclinical cure outcomes (ie clinical success) were obtained
Two US Acute Otitis Media Studies Clarithromycin vs AntimicrobialBeta-lactamase Inhibitor EFFICACY RESULTS PATHOGEN OUTCOME S pneumoniae clarithromycin success rate 4351 (84) control 5556 (98) H influenzae clarithromycin success rate 3645 (80) control 3133 (94) M catarrhalis clarithromycin success rate 910 (90) control 66 S pyogenes clarithromycin success rate 33 control 55 Overall clarithromycin success rate 91109 (83) control 97100 (97) Of the H influenzae isolated pre-treatment 3 were resistant to clarithromycin and 10 were resistant to the control agent
Safety
The incidence of adverse events in all patients treated primarily diarrhea (15 vs 38) and diaper rash (3
vs 11) in young children was clinically and statistically lower in the clarithromycin arm versus the control
arm
Duodenal Ulcer Associated with H pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Two US randomized double-blind clinical studies in patients with H pylori and duodenal ulcer disease
(defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for
eradication of H pylori Based on the results of these studies the safety and efficacy of the following
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
Treatment was for 14 days H pylori eradication was defined as two negative tests (culture and histology) at 4
to 6 weeks following the end of treatment
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating
H pylori Eradication of H pylori has been shown to reduce the risk of duodenal ulcer recurrence
A randomized double-blind clinical study performed in the US in patients with H pylori and duodenal ulcer
disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of
clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days This
study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating
H pylori
H pylori Eradication Rates-Triple Therapy (BIAXINlansoprazoleamoxicillin) Percent of Patients Cured [95 Confidence Interval] (number of patients)
Study
M93-131
M95-392
Duration
14 days
14 days
Triple Therapy Evaluable Analysis
92dagger [800-977] (n = 48)
86Dagger [757-936] (n = 66)
Triple Therapy Intent-to-Treat Analysis
86dagger [733-935] (n = 55)
83Dagger [720-908] (n = 70)
M95-399para 14 days 85 [770-910]
(N = 113) 82 [739-881]
(N = 126)
10 days 84 [760-898]
(N = 123) 81 [739-876]
(N = 135) Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD Bentley Australia) histology andor culture Patients were included in the analysis if they completed the study Additionally if patients were dropped out of the study due to an adverse event related to the study drug they were included in the analysis as evaluable failures of therapy Patients were included in the analysis if they had documented H pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year) All dropouts were included as failures of therapy dagger (p lt 005) versus BIAXINlansoprazole and lansoprazoleamoxicillin dual therapy Dagger (p lt 005) versus BIAXINamoxicillin dual therapy
para The 95 confidence interval for the difference in eradication rates 10-day minus 14-day is (-105 81) in the evaluable analysis and (-97 91) in the intent-to-treat analysis
Clarithromycin + Omeprazole and Amoxicillin Therapy
H pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence
Three US randomized double-blind clinical studies in patients with H pylori infection and duodenal ulcer
disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus
amoxicillin Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer and
the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years but without an
ulcer present at the time of enrollment The dosage regimen in the studies was clarithromycin 500 mg bid
Reference ID 3126038
plus omeprazole 20 mg bid plus amoxicillin 1 gram bid for 10 days In Studies 126 and 127 patients who
took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg qd Endpoints studied
were eradication of H pylori and duodenal ulcer healing (studies 126 and 127 only) H pylori status was
determined by CLOtestreg histology and culture in all three studies For a given patient H pylori was
considered eradicated if at least two of these tests were negative and none was positive The combination of
clarithromycin plus omeprazole and amoxicillin was effective in eradicating H pylori
Per-Protocol and Intent-to-Treat H pylori Eradication Rates of Patients Cured [95 Confidence Interval] Clarithromycin + omeprazole + amoxicillin
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
dagger Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127 history of ulcer within 5 years study M96-446) and H pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtestreg histology andor culture Patients were included in the analysis if they completed the study Additionally if patients dropped out of the study due to an adverse event related to the study drug they were included in the analysis as failures of therapy The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer Dagger Patients were included in the analysis if they had documented H pylori infection at baseline and had confirmed duodenal ulcer disease All dropouts were included as failures of therapy p lt 005 versus clarithromycin plus amoxicillin
Safety
In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin no adverse
reactions peculiar to the combination of these drugs have been observed Adverse reactions that have occurred
have been limited to those that have been previously reported with clarithromycin omeprazole or amoxicillin
The most frequent adverse experiences observed in clinical trials using combination therapy with
clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14) taste perversion (10) and
headache (7)
For information about adverse reactions with omeprazole or amoxicillin refer to the ADVERSE
REACTIONS section of their package inserts
Clarithromycin + Omeprazole Therapy
Four randomized double-blind multi-center studies (067 100 812b and 058) evaluated clarithromycin 500
mg tid plus omeprazole 40 mg qd for 14 days followed by omeprazole 20 mg qd (067 100 and 058) or
by omeprazole 40 mg qd (812b) for an additional 14 days in patients with active duodenal ulcer associated
with H pylori Studies 067 and 100 were conducted in the US and Canada and enrolled 242 and
256 patients respectively H pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive
5 Chaisson RE et al Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of
Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection AIDS 199711311shy
317
6 Kemper CA et al Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral
Regimen Ann Intern Med 1992116466-472
Filmtab ndash Film-sealed tablets Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd by Abbott Pharmaceuticals PR Ltd Barceloneta PR 00617
Biaxin Granules for Oral Suspension 125mg5mL and 250mg5mL Mfd by Abbott Laboratories North Chicago IL 60064
For Abbott Laboratories North Chicago IL 60064 USA
Reference ID 3126038
and 228 patients in Study 100 These studies compared the combination regimen to omeprazole and
clarithromycin monotherapies Studies 812b and 058 were conducted in Europe and enrolled 154 and 215
patients respectively H pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b
and 208 patients in Study 058 These studies compared the combination regimen to omeprazole monotherapy
The results for the efficacy analyses for these studies are described below
Duodenal Ulcer Healing
The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal
ulcer
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (nN) Study Clarithromycin +
Omeprazole Omeprazole Clarithromycin
US Studies
Study 100
Study 067
94 (5862)dagger
88 (5664)dagger 88 (6068)
85 (5565)
71 (4969)
64 (4469)
Non-US Studies Study 058
Study 812b1 99 (8485)
100 (6464)
95 (8286)
99 (7172)
NA
NA
dagger p lt 005 for clarithromycin + omeprazole versus clarithromycin monotherapy 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28
Eradication of H pylori Associated with Duodenal Ulcer
The combination of clarithromycin and omeprazole was effective in eradicating H pylori
H pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (nN) Study Clarithromycin + Omeprazole Omeprazole Clarithromycin US Studies
Study 100 64 (3961)daggerDagger 0 (059) 39 (1744)
Study 067 74 (3953)daggerDagger 0 (054) 31 (1342)
Non-US Studies
Study 058 74 (6486)Dagger 1 (190) NA
Study 812b 83 (5060)Dagger 1 (174) NA
dagger Statistically significantly higher than clarithromycin monotherapy (p lt 005) Dagger Statistically significantly higher than omeprazole monotherapy (p lt 005)
H pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of
treatment and two negative tests were required to be considered eradicated In the per-protocol analysis the
following patients were excluded dropouts patients with major protocol violations patients with missing H
pylori tests post-treatment and patients that were not assessed for H pylori eradication at 4 weeks after the
end of treatment because they were found to have an unhealed ulcer at the end of treatment
Reference ID 3126038
Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were
healed post-treatment
Ulcer Recurrence at 6 months by H pylori Status at 4-6 Weeks H pylori Negative H pylori Positive